ANILINE DERIVATIVES

Abstract: The invention concerns an aniline derivative of formula (I) wherein R<4> includes hydrogen and (1-4C)alkyl; R<5> includes hydrogen and (1-4C)alkyl; R<6> is hydrogen or (1-4C)alkyl; X<3> includes a group of the formula CR<7>R<8> wherein R<7> is hydrogen or (1-4C)alkyl and R<8> is hydrogen or (1-4C)alkyl; A<1> includes a direct link to X<1>; X<1> includes thio and sulphonyl; Ar includes phenylene, which may be optionally substituted; R<1> includes hydrogen and (1-4C)alkyl; and R<2> and R<3> together form a ring having 5 to 6 ring atoms including one oxygen atom, and which ring may bear one, two or three substituents, including methyl alpha to the oxygen atom; or a pharmaceutically acceptable salt thereof; processes for their preparation; pharmaceutical compositions containing them and their use as 5-lipoxygenase inhibitors.

Description: ANILINE DERIVATIVES This invention concerns aniline derivatives and more particularly aniline derivatives which are inhibitors of the enzyme 5-lipoxygenase (hereinafter referred to as 5-LO). The invention also concerns processes for the manufacture of said aniline derivatives and novel pharmaceutical compositions containing them. Also included in the invention is the use of said aniline derivatives in the treatment of various diseases such as inflammatory and/or allergic diseases in which the direct or indirect products of 5-LO catalysed oxidation of arachidonic acid are involved, and the production of new medicaments for such use. As stated above the aniline derivatives described hereinafter are inhibitors of 5-LO, which enzyme is known to be involved in catalysing the oxidation of arachidonic acid to give rise via a cascade process to the physiologically active leukotrienes such as leukotriene B, (LTB.) and the peptido-lipid leukotrienes such as leukotriene C, (LTC,) and leukotriene D, (LTD.) and various metabolites. The biosynthetic relationship and physiological properties of the leukotrienes are summarised by G.W. Taylor and S.R. Clarke in Trends in Pharmacological Sciences, 1986, _, 100-103. The leukotrienes and their metabolites have been implicated in the production and development of various diseases, for example various inflammatory and allergic diseases such as inflammation of the joints (especially rheumatoid arthritis, osteoarthritis and gout), inflammation of the gastrointestinal tract (especially inflammatory bowel disease, ulcerative colitis and gastritis), skin diseases (especially psoriasis, eczema and dermatitis), ocular conditions (especially allergic conjunctivitis and uveitis) and respiratory disease (especially asthma, bronchitis and allergic rhinitis), for example in the production and development of various cardiovascular and cerebrovascular disorders such as myocardial infarction, the formation of atherosclerotic plaques, hypertension, platelet aggregation, angina, stroke, reperfusion injury, vascular injury including restenosis and peripheral vascular disease, for example in the formation of the conditions of shock or trauma such as can follow burn injuries, toxaemia or surgery, and for example various disorders of bone metabolism such as osteoporosis (including senile and post enopausal osteoporosis), Paget's disease, bone metastases, hypercalcaemia, hyperparathyroidism, osteosclerosis, osteopetrosis and periodontitis, and the abnormal changes in bone metabolism which may accompany rheumatoid arthritis and osteoarthritis. In addition the leukotrienes are mediators of inflammatory diseases by virtue of their ability to modulate lymphocyte and leukocyte function. Other physiologically active metabolites of arachidonic acid, such as the prostaglandins and thromboxanes, arise via the action of the enzyme cyclooxygenase on arachidonic acid. It is disclosed in European Patent Application Nos. 0375404 A2 and 0385662 A2 that certain heterocyclic derivatives possess inhibitory properties against 5-L0. Furthermore European Patent Applications Nos. 0409413 and 0420511 are also concerned with heterocyclic derivatives which possess inhibitory properties against 5-LO. We have now discovered that certain aniline derivatives which possess some structural features which are similar to those of the compounds disclosed in the above-mentioned applications but which possess other structural features, in particular an ortho-substituted aniline group, which were not envisaged in those earlier applications are effective inhibitors of the enzyme 5-LO and thus of leukotriene biosyntheses. Thus such compounds are of value as therapeutic agents in the treatment of, for example, allergic conditions, psoriasis, asthma, cardiovascular and cerebrovascular disorders, and/or inflammatory and arthritic conditions, and/or disorders of bone metabolism, mediated alone or in part by one or more leukotrienes. According to the invention there is provided an aniline derivative of the formula I wherein R is hydrogen, (l-4C)alkyl, halogeno-(l-4C)alkyl, cyano-(l-4C)alkyl, hydroxy-(2-4C)alkyl, amino-(2-4C)alkyl, (l-4C)alkylamino-(2-4C)alkyl, di-[(l-4C)alkyl]amino-(2-4C)alkyl or phenyl-(l-4C)alkyl, and wherein said phenyl-(l-4C)alkyl group may optionally bear one or two substituents selected from halogeno, trifluoromethyl, cyano, (l-4C)alkyl and (l-4C)alkoxy; R is hydrogen, hydroxy, (l-4C)alkyl or (l-4C)alkoxy; R is hydrogen or (l-4C)alkyl; 3 7 8 X is oxy, thio, sulphinyl, sulphonyl or a group of the formula CR R 7 8 wherein R is hydrogen or (l-4C)alkyl and R is hydrogen or 3 9 9 (l-4C)alkyl, or X is a group of the formula NR wherein R is 3 hydrogen or (l-4C)alkyl, or X is a direct link to the 2-position of the anilino ring; the anilino ring may optionally bear a halogeno substituent; A is a direct link to X or is (l-3C)alkylene; X is oxy, thio, sulphinyl or sulphonyl; Ar is phenylene, pyridinediyl, pyrimidinediyl, thiophenediyl, furandiyl, thiazolediyl, oxazolediyl, thiadiazolediyl or oxadiazolediyl which may optionally bear one or two substituents selected from halogeno, cyano, trifluoromethyl, hydroxy, amino, (l-4C)alkyl, (l-4C)alkoxy, (l-4C)alkylamino and di-(l-4C)alkylamino; R is hydrogen, (l-4C)alkyl, (3-4C)alkenyl or (3-4C)alkynyl; and R 2 and R3 together form a group of the formula -A2-X2-A3- which 2 3 together with the carbon atom to which A and A are attached define a 2 3 ring having 5 or 6 ring atoms, wherein A and A , which may be the 2 same or different, each is (l-3C)alkylene and X is oxy, thio, sulphinyl, sulphonyl or imino, and which ring may bear one, two or three substituents, which may be the same or different, selected from hydroxy, (l-4C)alkyl, (l-4C)alkoxy, fluoro-(l-4C)alkyl, cyano-(l-4C)alkyl, (3-4C)alkenyl and (3-4C)alkynyl; 1 2 2 2 3 or R and R together form a group of the formula -A -X -A - which 2 together with the oxygen atom to which A is attached and the carbon 3 atom to which A is attached define a ring having 5 or 6 ring atoms, 2 3 wherein A and A , which may be the same or different, each is 2 (l-3C)alkylene and X is oxy, thio, sulphinyl or sulphonyl, and which 3 ring may bear one, two or three (l-4C)alkyl substituents, and R is ( l-4C)alkyl, (2-4C)alkenyl or (2-4C)alkynyl; or a pharmaceutically-acceptable salt, ester or amide thereof. In this specification the generic "alkyl" includes both straight-chain and branched-chain alkyl groups. However references to individual alkyl groups such as "propyl" are specific for the straight-chain version only and references to individual branched-chain alkyl groups such as "isopropyl" are specific for the branched-chain version only. An analogous convention applies to other generic terms. It is to be understood that, insofar as the compounds of the formula I defined above comprise an acidic carboxylic acid group and a basic anilino group and hence may exist partially or wholly in a zwitterionic form, the invention includes in its definition any neutral or zwitterionic form, or a mixture thereof, of a compound of the formula I. The invention is not to be limited merely to any one form utilised for convenience within the formulae drawings or for the purpose of naming particular compounds of the invention. It is further to be understood that, insofar as certain of the compounds of formula I defined above may exist in optically active or racemic forms by virtue of one or more asymmetric carbon atoms, the invention includes in its definition any such optically active or racemic form which possesses the property of inhibiting 5-LO. The synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form. Suitable values for the generic terms referred to above include those set out below. 4 A suitable value for R when it is (l-4C)alkyl is, for example, methyl, ethyl, propyl, isopropyl or butyl; when it is halogeno-(1-4C)alkyl is, for example, 2-fluoroethyl, 2-chloroethyl, 2,2,2-trifluoroethyl, 3-fluoropropyl or 3-chloropropyl; when it is cyano-(l-4C)alkyl is, for example, cyanomethyl, 2-cyanoethyl and 3-cyanopropyl; when it is hydroxy-(2-4C)allyl is, for example, 2-hydroxyethyl and 3-hydroxypropyl; when it is amino-(2-4C)alkyl is, for example, 2-aminoethyl and 3-aminopropyl; when it is (l-4C)alkylamino-(2-4C)alkyl is, for example, 2-methylaminoethyl, 2-ethylaminoethyl or 3-methylaminopropyl; when it is di-[(l-4C)allcyl]amino-(2-4C)alkyl is, for example, 2-dimethylaminoethyl, 2-diethylaminoethyl, 2-(N-ethyl-N-methylamino)ethyl or 3-dimethylaminopropyl; and when it is phenyl-(l-4C)alkyl is, for example, benzyl, phenethyl or 3-phenylpropyl. A suitable value for R or R when it is (1-4C)alkyl, or for the (l-4C)alkyl group in X 3 when X3 is a group of the formula CR7R8 or 9 7 8 9 .NR and R , R or R is (1-4C)alkyl, is, for example, methyl or ethyl. A suitable value for R when it is (l-4C)alkoxy is, for example, methoxy or ethoxy. A suitable value for A when it is (l-3C)alkylene is, for eχ.ample, methylene, ethylene or trimethylene. A suitable value for Ar when it is phenylene is, for example, 1,3- or 1,4-phenylene. A suitable value for Ar when it is pyridinediyl, pyrimidinediyl, thiophenediyl, furandiyl, thiazolediyl, oxazolediyl, thiadiazolediyl or oxadiazolediyl is, for example, 2,4-, 2,5- or 3,5-pyridinediyl, 4,6-pyrimidinediyl, 2,4- or 2,5-thiophenediyl, 2,4- or 2,5-furandiyl, 2,4- or 2,5-thiazolediyl, 2,4- or 2,5-oxazolediyl, 2,5-thiadiazolediyl or 2,5-oxadiazolediyl. Suitable values for substituents which may be present when 4 R is phenyl-(l-4C)allyl or for substituents on the anilino ring or on Ar include, for example:- for halogeno: fluoro, chloro and bromo; for (1-4C)alkyl: methyl, ethyl, propyl and isopropyl; for (l-4C)alkoxy: methoxy, ethoxy, propoxy and isopropoxy; for (l-4C)alkylamino: methylamino, ethyla ino and propylamino; for di-(l-4C)alkylamino: dimethylamino, diethylamino and N-ethyl-N-methylamino. A suitable value for R when it is (l-4C)alkyl is, for example, methyl, ethyl, propyl or butyl; when it (3-4C)alkenyl is, for example allyl, 2-butenyl or 3-butenyl; and when it is (3-4C)alkynyl is, for example, 2-propynyl or 2-butynyl. 2 3 When R and R together form a group of the formula -A -X -A - which together with the carbon atom to which A and A are attached define a ring having 5 or 6 ring atoms then a suitable value 2 3 for A or A , which may be the same or different, when each is (l-3C)alkylene is, for example, methylene, ethylene or trimethylene. Suitable values for the substituents which may be present on said 5- or 6-membered ring include, for example:- for (l-4C)alkyl: methyl, ethyl, propyl, isopropyl, butyl and isobutyl; for (l-4C)alkoxy: methoxy, ethoxy, propoxy, isopropoxy and butoxy; for fluoro-(l-4C)alkyl: trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl and 3,3,3-trifluoroethyl; for cyano-(1-4C)alkyl: cyanomethyl and 2-cyanoethyl; for (3-4C)alkenyl: allyl; and for (3-4C)alkynyl: 2-propynyl. Said substituents may be located on any available position including, when the substituent is, for example, (1-4C)alkyl, 2 fluoro-(l-4C)alkyl and (3-4C)alkynyl, on the nitrogen atom when X is lmmo. 1 2 When R and R together form a group of the formula 2 2 3 2 -A -X -A - which together with the oxygen atom to which A is attached 3 and with the carbon atom to which A is attached define a ring having 2 3 5 or 6 ring atoms then a suitable value for A and A , which may be the same or different, when each is (l-3C)alkylene is, for example, methylene, ethylene or trimethylene. Suitable values for the (1-4C)alkyl substituents which may be present on said 5- or 6-membered ring include, for example, methyl, ethyl, propyl, isopropyl and butyl. 3 A suitable value for R when it is (1-4C)alkyl is, for example, methyl, ethyl, propyl or butyl; when it is (2-4C)alkenyl is, for example, vinyl, allyl, 2-butenyl or 3-butenyl; and when it is (2-4C)alkynyl is, for example, ethynyl, 2-propynyl or 2-butynyl. A suitable pharmaceutically-acceptable salt of a compound of the invention is, for example, an acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic, citric or maleic acid. In addition a suitable pharmaceutically-acceptable salt of a compound of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt such as ammonium or tetramethylammonium or a salt with an organic base which affords a physiologically-acceptable cation, for example a salt with ethylamine, diethylamine, triethylamine or piperidine. A suitable pharmaceutically-acceptable ester of a compound of the invention is, for example, an ester formed by the esterification of the carboxy group of the compound of the formula I with an alcohol, for example a (l-6C)alcohol such as methanol, ethanol, ethylene glycol, propanol or tert-butanol, or with a phenol or phenyl-(l-4C)alcohol such as phenol or benzyl alcohol or a substituted phenol or phenyl-(l-4C)alcohol wherein each substituent is selected from, for example, a halogeno (such as fluoro or chloro), (l-4C)alkyl (such as methyl) or (l-4C)alkoxy (such as methoxy) group. A further suitable pharmaceutically-acceptable ester of a compound of the invention is, for example, an ester formed by the reaction of a hydroxy group within a compound of the formula I, for example, the hydroxy group formed when R is hydrogen, with, for example, a carboxylic acid, for example a (2-5C)alkanoic acid such as acetic acid or propionic acid, or, for example a benzoic acid or a substituted benzoic acid wherein each substituent is selected from, for example, a halogeno (such as fluoro or chloro), (l-4C)alkyl (such as methyl) or (l-4C)alkoxy (such as methoxy) group. A suitable pharmaceutically-acceptable amide of a compound of the invention is, for example, an amide formed by the amidification of the carboxy group of the compound of the formula I with an amine, for example, a (l-6C)alkylamine such as methylamine, ethylamine or propyla ine or a di-(l-6C)alkylamine such as dimethylamine, diethylamine or N-ethyl-N-methylamine. Particular novel compounds of the invention are, for example, aniline derivatives of the formula I, or pharmaceutically-acceptable salts, esters or amides thereof, wherein the variable groups R 4 , R 5 , R 6 , X 3 , A 1 , X 1 , Ar, R 1 , R 2 and R 3 have the values disclosed hereinbefore or hereinafter in this section defining particular compounds of the invention:- (a) R 4 is (l-4C)alkyl; (b) R is hydrogen or (l-4C)alkyl; (c) R is hydrogen or (1-4C)alkyl; 3 7 8 (d) X is oxy or thio or a group of the formula CR R wherein 7 8 3 each of R and R is hydrogen, or X is a direct link to the 2-position of the anilino ring; 3 7 8 7 8 (e) X is a group of the formula CR R wherein each of R and R 3 is hydrogen, or X is a direct link to the 2-position of the anilino ring; (f) A is (l-3C)alkylene and X is oxy; (g) A is a direct link to X and X is oxy, thio, sulphinyl or sulphonyl; (h) Ar is phenylene which may optionally bear one or two substituents selected from halogeno, trifluoromethyl, (1-4C)alkyl and (l-4C)alkoxy; (i) Ar is pyridinediyl or pyrimidinediyl which may optionally bear one amino substituent; (j) Ar is thiophenediyl or thiazolediyl; (k) R is hydrogen; (1) R 1 is (l-4C)alkyl or (3-4C)alkenyl; 2 3 2 2 3 (m) R and R together form a group of the formula -A -X -A - 2 3 which together with the carbon atom to which A and A are attached 2 3 define a ring having 5 or 6 ring atoms, wherein each of A and A is 2 independently (l-3C)alkylene and X is oxy, and which ring may bear one or two (l-4C)alkyl substituents; or 1 2 2 2 3 (n) R and R together form a group of the formula -A -X -A - 2 which together with the oxygen atom to which A is attached and with 3 the carbon atom to which A is attached define a ring having 5 ring 2 3 2 atoms, wherein each of A and A is methylene and X is oxy, and which 3 ring may bear one or two methyl substituents, and R is methyl or ethyl. A preferred compound of the invention comprises an aniline derivative of the formula I 4 wherein R is methyl, ethyl or propyl; R is hydrogen or methyl; R is hydrogen or methyl; 3 7 8 7 X is oxy or thio or a group of the formula CR R wherein each of R o and R is hydrogen; A is methylene and X is oxy, or A is a direct link to X and X is oxy, thio, sulphinyl or sulphonyl; Ar is 1,3- or 1,4-phenylene which may optionally bear one or two substituents selected from fluoro, chloro, trifluoromethyl, methyl and methoxy, or Ar is 3,5-pyridinediyl, 4,6-pyrimidinediyl, 2-amino-4,6-pyrimidinediyl, 2,4- or 2,5-thiophenediyl or 2,4- or 2,5-thiazolediyl; R is hydrogen, methyl, ethyl or allyl; and R 2 and R3 together form a group of the formula -A2-X2-A3- which 2 3 together with the carbon atom to which A and A are attached define a 2 3 ring having 5 or 6 ring atoms, wherein A is methylene or ethylene, A 2 is ethylene and X is oxy, and which ring may bear one or two substituents selected from methyl and ethyl; or a pharmaceutically-acceptable salt thereof. A further preferred compound of the invention comprises an aniline derivative of the formula I 4 wherein R is methyl, ethyl or propyl; R is hydrogen or methyl; R is hydrogen or methyl; 3 7 8 7 8 X is a group of the formula CR R wherein each of R and R is hydrogen; A is methylene and X is oxy, or A is a direct link to X and X is oxy, thio, sulphinyl or sulphonyl; Ar is 1,3- or 1,4-phenylene which may optionally bear one or two substituents selected from fluoro, chloro, trifluoromethyl, methyl and methoxy, or Ar is 3,5-pyridinediyl, 4,6-pyrimidinediyl, 2-amino-4,6-pyrimidinediyl, 2,4- or 2,5-thiophenediyl or 2,4- or 2,5-thiazolediyl; R is hydrogen, methyl, ethyl or allyl; and 2 3 2 2 3 R and R together form a group of the formula -A -X -A - which 2 3 together with the carbon atom to which A and A are attached define a 2 3 ring having 5 or 6 ring atoms, wherein A is methylene or ethylene, A 2 is ethylene and X is oxy, and which ring may bear one or two substituents selected from methyl and ethyl; or a pharmaceutically-acceptable salt thereof. A further preferred compound of the invention comprises an aniline derivative of the formula I 4 wherein R is methyl or ethyl; 5 R is hydrogen; R is hydrogen; 3 X is oxy or CH„; 1 1 1 A is a direct link to X and X is thio or sulphonyl; Ar is 1,3-phenylene, 5-fluoro-l,3-phenylene, 2,4-thiophenediyl (with the X group in the 2-position), 2,5-thiophenediyl, 2,4-thiazolediyl (with the X group in the 2-position) or 2,5-thiazolediyl (with the X group in the 2-position); R is hydrogen or methyl; and 2 3 2 2 3 R and R together form a group of the formula -A -X -A - which 2 3 together with the carbon atom to which A and A are attached define a 2 3 ring having 5 or 6 ring atoms, wherein A is methylene or ethylene, A 2 is ethylene and X is oxy, and which ring may bear a methyl 2 substituent alpha to X ; or a pharmaceutically-acceptable salt thereof. A further preferred compound of the invention comprises an aniline derivative of the formula I 4 wherein R is methyl or ethyl; R is hydrogen; R is hydrogen; X 3 is CH„; A 1 is a direct link to X1 and X1 is thio or sulphonyl; Ar is 1,3-phenylene, 5-fluoro-l,3-phenylene, 2,4-thiophenediyl (with the X group in the 2-position), 2,5-thiophenediyl, 2,4-thiazolediyl (with the X group in the 2-position) or 2,5-thiazolediyl (with the X group in the 2-position) ; R is hydrogen or methyl; and 2 3 2 2 3 R and R together form a group of the formula -A -X -A - which 2 3 together with the carbon atom to which A and A are attached define a 2 3 ring having 5 or 6 ring atoms, wherein A is methylene or ethylene, A 2 is ethylene and X is oxy, and which ring may bear a methyl 2 substituent alpha to X ; or a pharmaceutically-acceptable salt thereof. A further preferred compound of the invention comprises an aniline derivative of the formula I 4 wherein R is methyl; R is hydrogen; R is hydrogen; X 3 is CH_; 1 1 1 A is a direct link to X and X is thio or sulphonyl; Ar is 1,3-phenylene or 5-fluoro-l,3-phenylene; R is methyl; and 2 3 2 2 3 R and R together form a group of the formula -A -X -A - which together with the carbon atom to which A 2 and A3 are attached define a 2 3 2 ring having 6 ring atoms, wherein each of A and A is ethylene and X 2 is oxy, and which ring may bear a methyl substituent alpha to X ; or a pharmaceutically-acceptable salt thereof. A specific especially preferred compound of the invention is, for example, the following aniline derivative of the formula I, or a pharmaceutically-acceptable salt thereof:- 3-{5-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]-2- methylaminophenyljpropionic acid; (2S,4R)-3-{5-[5-fluoro-3-(4-methoxy-2-methyltetrahydropyran-4-yl)- phenylthio]-2-methylaminophenyl}propionic acid; (2S,4R)-3-{5-[5-fluoro-3-(4-methoxy-2-methyltetrahydropyran-4-yl)- phenylsulphonyl]-2-methylaminophenyl}propionic acid; or (2S,4R)-3-{5-[3-(4-hydroxy-2-methyltetrahydropyran-4-yl)phenylthio]-2- methylaminophenyljpropionic acid. A compound of the invention comprising an aniline derivative of the formula I, or a pharmaceutically-acceptable salt, ester or amide thereof, may be prepared by any process known to be applicable to the preparation of structurally-related compounds. Such procedures are provided as a further feature of the invention and are illustrated by the following representative examples in which, unless otherwise stated, R 4 , R 5 , R 6 , X 3 , A 1 , X 1 , Ar, R 1 , R 2 and R 3 have any of the meanings defined hereinbefore, provided that when there is an amino, imino, alkylamino, carboxy or hydroxy group in a compound of the invention then any such group may optionally be protected by a conventional protecting group which may be removed when so desired by conventional means. (a) The coupling, conveniently in the presence of a suitable base, of a compound of the formula II R with a compound of the formula III OR 1 Z-Ar- C— R 2 III R 3 wherein Z is a displaceable group. A suitable displaceable group Z is, for example, a halogeno or sulphonyloxy group, for example a fluoro, chloro, bromo, iodo, methane- sulphonyloxy or toluene-£-sulphonyloxy group. A suitable base for the coupling reaction is, for example, an alkali or alkaline earth metal carbonate, (l-4C)alkoxide, hydroxide or hydride, for example sodium carbonate, potassium carbonate, sodium ethoxide, potassium butoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride or potassium hydride, or an organometallic base such as (l-4C)alkyl-lithium, for example n-butyl-lithium. The coupling reaction is conveniently performed in a suitable inert solvent or diluent, for example N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one, dimethylsulphoxide, acetone, 1,2-dimethoxyethane or tetrahydrofuran, and at a temperature in the range, for example, 10 to 150 C, conveniently at or near 100°C. Conveniently the reaction may be performed in the presence of a suitable catalyst, for example a metallic catalyst, for example palladium(O) or copper(I) such as tetrakis(triphenylphosphine)- palladium, cuprous chloride or cuprous bromide. A suitable protecting group for an amino, imino or alkylamino group is, for example, an acyl group for example a (2-4C)alkanoyl group (especially acetyl), a (l-4C)alkoxycarbonyl group (especially methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl) , an arylmethoxycarbonyl group (especially benzyloxycarbonyl) or an aroyl group (especially benzoyl). The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-charcoal. A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a (l-4C)alkyl group (especially methyl or ethyl) which may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. A suitable protecting group for a hydroxy group is, for example, an acyl group, for example a (2-4C)alkanoyl group (especially acetyl), an aroyl group (especially benzoyl) or an arylmethyl group (especially benzyl). The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting 14 group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-charcoal. The starting materials of the formulae II and III may be obtained by standard procedures of organic chemistry. The preparation of such starting materials may be achieved by analogous procedures to those illustrated within the accompanying non-limiting Examples. The disclosures of European Patent Applications Nos. 0375404, 0385662, 0409413, 0420511, 0462812 and 0462813 are particularly relevant to the preparation of suitable starting materials. (b) The coupling, conveniently in the presence of a suitable base as defined hereinbefore, of a compound of the formula IV R 6 wherein Z is a displaceable group as defined hereinbefore, with a compound of the formula V OR 1 H- X - Ar- C— R V The coupling reaction is conveniently performed in a suitable inert solvent or diluent as defined hereinbefore and at a temperature in the range, for example, 10 to 150 C, conveniently at or near 100°C. The reaction may conveniently be performed in the presence of a suitable catalyst as defined hereinbefore. The starting materials of the formulae IV and V may be obtained by standard procedures of organic chemistry. The preparation of such starting materials may be achieved by analogous procedures to those illustrated within the accompanying non-limiting Examples. The disclosures of European Patent Applications Nos. 0375404, 0385662, 0409413, 0420511, 0462812 and 0462813 are particularly relevant to the preparation of suitable starting materials. (c) The coupling of a compound of the formula VI wherein Z is a displaceable group as defined hereinbefore, with an organometallic reagent of the formula VII OR M -Ar- C— R 2 VII R ' wherein M is an alkali metal or alkaline earth metal such as lithium or calcium or M represents the magnesium halide portion of a conventional Grignard reagent. The coupling reaction is conveniently performed in a suitable inert solvent or diluent as defined hereinbefore and at a temperature in the range, for example, -80 to +50°C, conveniently in the range -80°C to ambient temperature. The preparation of the starting materials of the formulae VI and VII may be achieved by analogous procedures to those illustrated within the accompanying non-limiting Examples. Alternatively such starting materials may be obtained by standard procedures of organic chemistry, (d) The hydrolysis, conveniently in the presence of a suitable base as defined hereinbefore, of a compound of the formula VIII The hydrolysis reaction is conveniently performed in a suitable inert solvent or diluent as defined hereinbefore and at a temperature in the range, for example, 10 to 180°C, conveniently in the range 100 to 150°C. The preparation of the starting materials of the formula VIII is described within the accompanying non-limiting Examples which are provided for the purpose of illustration only. (e) For the production of those compounds of the formula I wherein X 1 or X3 is a sulphinyl or sulphonyl group, wherein R2 and R3 2 2 3 2 together form a group of the formula -A -X -A - and X is a sulphinyl 1 2 .or sulphonyl group or wherein R and R together form a group of the 2 2 3 2 formula -A -X -A - and X is a sulphinyl or sulphonyl group, the 1 3 oxidation of a compound of the formula I wherein X or X is a thio 2 3 group, wherein R and R together form a group of the formula 2 2 3 2 1 2 -A -X -A - and X is a thio group or wherein R and R together form a 2 2 3 2 group of the formula -A -X -A - and X is a thio group. A suitable oxidising agent is, for example, any agent known in the art for the oxidation of thio to sulphinyl and/or sulphonyl, for example, hydrogen peroxide, a peracid (such as 3-chloroperoxybenzoic or peroxyacetic acid), an alkali metal peroxysulphate (such as potassium peroxymonosulphate) , a di-(l-4C)alkyldioxiran (such as dimethyldioxiran) , chromium trioxide or gaseous oxygen in the presence of platinum. The oxidation is generally carried out under as mild conditions as possible and with the required stoichiometric amount of oxidising agent in order to reduce the risk of over oxidation and damage to other functional groups. In general the reaction is carried out in a suitable solvent or diluent such as methylene chloride, chloroform, acetone, tetrahydrofuran or tert-butyl methyl ether and at a temperature, for example, at or near ambient temperature, that is in the range 15 to 35°C. When a compound carrying a sulphinyl group is required a milder oxidising agent may also be used, for example sodium or potassium metaperiodate, conveniently in a polar solvent such as acetic acid or ethanol. It will be appreciated that when a compound of the formula I containing a sulphonyl group is required, it may be obtained by oxidation of the corresponding sulphinyl compound as well as of the corresponding thio compound. When a pharmaceutically-acceptable salt of a compound of the formula I is required, it may be obtained, for example, by reaction of said compound with a suitable acid or base using a conventional procedure. When a pharmaceutically-acceptable ester of a compound of the formula I is required it may be obtained, for example, by reaction of a carboxy group within said compound with a suitable alcohol or phenol using a conventional procedure or by reaction of a hydroxy group within said compound with a suitable carboxylic acid using a conventional procedure. When a pharmaceutically-acceptable amide of a compound of the formula I is required it may be obtained, for example, by reaction of a carboxy group within said compound with a suitable amine using a conventional procedure. When an optically active form of a compound of the formula I is required, it may be obtained by carrying out one of the aforesaid procedures using an optically active starting material, or by resolution of a racemic form of said compound using a conventional procedure. As stated previously, the compounds of the formula I are inhibitors of the enzyme 5-LO. The effects of this inhibition may be demonstrated using one or more of the standard procedures set out below:- a) An in vitro assay system involving incubating a test compound with heparinised human blood, prior to challenge with the calcium ionophore A23187 and then indirectly measuring the inhibitory effects on 5-LO by assaying the amount of LTB^, using specific radioimmunoassays described by Carey and Forder (Prostaglandins, Leukotrienes Hed. , 1986, 22, 57; Prostaglandins, 1984, 28, 666; Brit. J. Pharmacol., 1985, 84, 34P) which involves the use of a protein-LTB, conjugate produced using the procedure of Young et alia (Prostaglandins, 1983, 26(4), 605-613). The effects of a test compound on the enzyme cyclooxygenase (which is involved in the alternative metabolic pathway for arachidonic acid and gives rise to prostaglandins, thromboxanes and related metabolites) may be measured at the same time using the specific radioimmunoassay for thromboxane B 2 (TxB_) described by Carey and Forder (see above). This test provides an indication of the effects of a test compound against 5-LO and also cyclooxygenase in the presence of blood cells and proteins. It permits the selectivity of the inhibitory effect on 5-LO or cyclooxygenase to be assessed. b) An ex vivo assay system, which is a variation of test a) above, involving administration to a group of rats of a test compound (usually orally as the suspension produced when a solution of the test compound in dimethylsulphoxide is added to carboxy ethylcellulose) , blood collection, heparinisation, challenge with A23187 and radioimmunoassay of LTB, and TxB_. This test provides an indication of the bioavailability of a test compound as an inhibitor of 5-LO or cyclooxygenase. c) An in vivo system involving measuring the effects of a test compound administered orally to a group of male rats against the liberation of LTB, induced by zymosan within an air pouch generated within the subcutaneous tissue of the back of each rat. The rats are anaesthetised and air pouches are formed by the injection of sterile air (20 ml). A further injection of air (10 ml) is similarly given after 3 days. At 6 days after the initial air injection the test compound is administered (usually orally as the suspension produced when a solution of the test compound in dimethylsulphoxide is added to hydroxypropylmethylcellulose), followed by the intrapouch injection of zymosan (1 ml of a 1% suspension in physiological saline). After 3 hours the rats are killed, the air pouches are lavaged with physiological saline, and the specific radioimmunoassay described above is used to assay LTB, in the washings. This test provides an indication of inhibitory effects against 5-LO in an inflammatory milieu. Although the pharmacological properties of the compounds of the formula I vary with structural changes as expected, in general compounds of the formula I possess 5-LO inhibitory effects at the following concentrations or doses in one or more of the above tests a)-c):- Test a): IC 50 (LTB^) in the range, for example, 0.01-40μM ICC Q (TxB 2 ) in the range, for example, 40-200μM; Test b): oral ED 50 (LTB.) in the range, for example, O.l-lOOmg/kg; Test c): oral ED-..(LTB,) in the range, for example, 0.1-50mg/kg. No overt toxicity or other untoward effects are present in tests b) and/or c) when compounds of the formula I are administered at several multiples of their minimum inhibitory dose or concentration. Thus, by way of example, the compound sodium 3-{5-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]-2- methylaminophenyljpropionate has an IC of 1.3μM against LTB, in test a) and an oral ED,- n of <1.5 mg/kg versus LTB, in test c). In general those compounds of the formula I which are particularly preferred have an oral ED,_ n of <10 mg/kg against LTB, in tests b) and/or c). These compounds are examples of compounds of the invention which show selective inhibitory properties for 5-L0 as opposed to cyclooxygenase, which selective properties are expected to impart improved therapeutic properties, for example, a reduction in or freedom from the gastrointestinal side-effects frequently associated with cyclooxygenase inhibitors such as indomethacin. According to a further feature of the invention there is provided a pharmaceutical composition which comprises an aniline derivative of the formula I, or a pharmaceutically- acceptable salt thereof, in association with a pharmaceutically- acceptable diluent or carrier. The composition may be in a form suitable for oral use, for example a tablet, capsule, aqueous or oily solution, suspension or emulsion; for topical use, for example a cream, ointment, gel or aqueous or oily solution or suspension; for nasal use, for example a snuff, nasal spray or nasal drops; for vaginal or rectal use, for example a suppository; for administration by inhalation, for example as a finely divided powder such as a dry powder, a microcrystalline form or a liquid aerosol; for sub-lingual or buccal use, for example a tablet or capsule; or for parenteral use (including intravenous, subcutaneous, intramuscular, intravascular or infusion), for example a sterile aqueous or oily solution or suspension. In general the above compositions may be prepared in a conventional manner using conventional excipients. The amount of active ingredient (that is an aniline derivative of the formula I, or a pharmaceutically-acceptable salt thereof) that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 2 g of active agent compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition. Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient. According to a further feature of the invention there is provided an aniline derivative of the formula I, or a pharmaceutically-acceptable salt thereof, for use in a method of treatment of the human or animal body by therapy. The invention also includes a method of treating a disease or medical condition mediated alone or in part by one or more leukotrienes which comprises administering to a warm-blooded animal requiring such treatment an effective amount of an active ingredient as defined above. The invention also provides the use of such an active ingredient in the production of a new medicament for use in a leukotriene mediated disease or medical condition. The size of the dose for therapeutic or prophylactic purposes of a compound of the formula I will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine. As mentioned above, compounds of the formula I are useful in treating those diseases such as allergic and inflammatory conditions and disorders of bone metabolism which are due alone or in part to the effects of the metabolites of arachidonic acid arising by the linear (5-LO catalysed) pathway and in particular the leukotrienes, the production of which is mediated by 5-LO. As previously mentioned, such conditions include, for example, various inflammatory and allergic diseases such as inflammation of the joints (especially rheumatoid arthritis, osteoarthritis and gout), inflammation of the gastrointestinal tract (especially inflammatory bowel disease, ulcerative colitis and gastritis), skin diseases (especially psoriasis, eczema and dermatitis), ocular conditions (especially allergic conjunctivitis and uveitis) and respiratory disease (especially asthma, bronchitis and allergic rhinitis), for example in the production and development of various cardiovascular and cerebrovascular disorders such as myocardial infarction, the formation of atherosclerotic plaques, hypertension, platelet aggregation, angina, stroke, reperfusion injury, vascular injury including restenosis and peripheral vascular disease, for example in the formation of the conditions of shock or trauma such as can follow burn injuries, toxaemia or surgery, and for example various disorders of bone metabolism such as osteoporosis (including senile and postmenopausal osteoporosis), Paget's disease, bone metastases, hypercalcaemia, hyperparathyroidism, osteosclerosis, osteopetrosis and periodontitis, and the abnormal changes in bone metabolism which may accompany rheumatoid arthritis and osteoarthritis. In using a compound of the formula I for therapeutic or prophylactic purposes it will generally be administered so that a daily dose in the range, for example, 0.5 mg to 75 mg per kg body weight is received, given if required in divided doses. In general lower doses will be administered when a parenteral route is employed. Thus, for example, for intravenous administration, a dose in the range, for example, 0.5 mg to 30 mg per kg body weight will generally be used. Similarly, for administration by inhalation, a dose in the range, for example, 0.5 mg to 25 mg per kg body weight will be used. Although the compounds of the formula I are primarily of value as therapeutic agents for use in warm-blooded animals (including man), they are also useful whenever it is required to inhibit the enzyme 5-LO. Thus, they are useful as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents. By virtue of their effects on leukotriene production, the compounds of the formula I have certain cytoprotective effects, for example they are useful in reducing or suppressing certain of the adverse gastrointestinal effects of the cyclooxygenase inhibitory non- steroidal anti-inflammatory agents (NSAIA) , such as indomethacin, acetylsalicylic acid, ibuprofen, sulindac, tolmetin and piroxicam. Furthermore, co-administration of a 5-LO inhibitor of the formula I with a NSAIA can result in a reduction in the quantity of the latter agent needed to produce a therapeutic effect, thereby reducing the likelihood of adverse side-effects. According to a further feature of the invention there is provided a pharmaceutical composition which comprises an aniline derivative of the formula I, or a pharmaceutically-acceptable salt thereof as defined hereinbefore, in conjunction or admixture with a cyclooxygenase inhibitory non-steroidal antiinflammatory agent (such as those mentioned above), and a pharmaceutically-acceptable diluent or carrier. The cytoprotective effects of the compounds of the formula I may be demonstrated, for example in a standard laboratory model which assesses protection against indomethacin-induced or ethanol-induced ulceration in the gastrointestinal tract of rats. The compositions of the invention may in addition contain one or more therapeutic or prophylactic agents known to be of value for the disease under treatment. Thus, for example a known platelet aggregation inhibitor, hypolipidemic agent, anti-hypertensive agent, beta-adrenergic blocker or a vasodilator may usefully also be present in a pharmaceutical composition of the invention for use in treating a heart or vascular disease or condition. Similarly, by way of example, an anti-histamine, steroid (such as beclomethasone dipropionate) , sodium cromoglycate, phosphodiesterase inhibitor or a beta-adrenergic stimulant may usefully also be present in a pharmaceutical composition of the invention for use in treating a pulmonary disease or condition. The invention will now be illustrated in the following non-limiting Examples in which, unless otherwise stated:- (i) evaporations were carried out by rotary evaporation in vacuo and work-up procedures were carried out after removal of residual solids by filtration; (ii) operations were carried out at ambient temperature, that is in the range 18-25°C and under an atmosphere of an inert gas such as argon; (iii) column chromatography (by the flash procedure) and medium pressure liquid chromatography (MPLC) were performed on Merck Kieselgel silica (Art. 9385) or Merck Lichroprep RP-18 (Art. 9303) reversed-phase silica obtained from E. Merck, Darmstadt, Germany; (iv) yields are given for illustration only and are not necessarily the maximum attainable; (v) the structures of the end-products of the formula I were confirmed by NMR and mass spectral techniques; unless otherwise stated, CDC1, solutions of the end-products of the formula I were used for the determination of the NMR spectral data, chemical shift values were measured on the delta scale and the following abbreviations are used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; (vi) intermediates were not generally fully characterised and purity was assessed by thin layer chromatographic, infra-red (IR) or NMR analysis; (vii) melting points are uncorrected and were determined using a Mettler SP62 automatic melting point apparatus or an oil-bath apparatus; melting points for the end-products of the formula I were determined after recrystallisation from a conventional organic solvent such as ethanol, methanol, acetone, ether or hexane, alone or in admixture; (viii ) the following abbreviations have been used: - DMSO dimethylsulphoxide; NMP N-methylpyrrolidin-2-one; THF tetrahydrofuran; DMF N,N-dimethylformamide. Example 1 A mixture of 4-[5-fluoro-3-(l-methyl-2-oxo-l,2,3,4- tetrahydroquinolin-6-ylthio)phenyl]-4-methoxytetrahydropyran (0.3 g) , potassium hydroxide (0.23 g), water (0.5 ml) and DMSO (2 ml) was stirred and heated to 130°C for 1 hour. The mixture was cooled to ambient temperature. Water (10 ml) was added and the mixture was acidified to pH5 by the addition of dilute aqueous hydrochloric acid. The mixture was extracted with diethyl ether (10 ml). A solution of sodium hydroxide (0.03 g) in methanol (2 ml) was added and the mixture was evaporated. The residue was partitioned between diethyl ether (10 ml) and water (5 ml). The aqueous layer was evaporated. There was thus obtained sodium 3-{5-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)- phenylthio]-2-methylaminophenyl}propionate as a gum (0.2 g, 60%); NMR Spectrum (CD 3 SOCD 3 ) 1.8 (m, 4H), 2.15 (t, 2H) , 2.65 (t, 2H), 2.7 (s, 3H), 2.85 (s, 3H), 3.7 (m, 4H), 6.5-7.2 (m, 7H) . The 4-[5-fluoro-3-(l-methyl-2-oxo-1,2,3,4- tetrahydroquinolin-6-ylthio)phenyl]-4-methoxytetrahydropyran used as a starting material was obtained as follows:- A mixture of concentrated hydrochloric acid (5 drops) and water (50 ml) was added to a stirred mixture of di-(l-methyl-2-oxo- l,2,3,4-tetrahydroquinolin-6-yl) disulphide (European Patent Application No. 0462812, Example 7 thereof; 38.4 g), triphenylphosphine (29 g) and 1,4-dioxan (300 ml). The mixture was stirred at ambient temperature for 30 minutes. The mixture was concentrated by evaporation to reduce the volume by approximately one half. The residue was partitioned between ethyl acetate and 0.5N aqueous sodium hydroxide solution. The aqueous phase was washed with diethyl ether and then acidified to pH2 by the addition of dilute aqueous hydrochloric acid. The acidic mixture was extracted with ethyl acetate. The organic phase was dried (MgSO.) and evaporated. The residual oil was dissolved in diethyl ether and hexane was added. There was thus obtained 6-mercapto-l-methyl-1,2,3, -tetrahydro- quinolin-2-one as a solid (35.5 g, 92%) which was used without further purification. n-Butyl-lithium (1.4M in hexane, 1.5 ml) was added dropwise to a stirred mixture of 6-mercapto-l-methyl-l,2,3,4-tetrahydro- quinolin-2-one (0.386 g) , 4-(3,5-difluorophenyl)-4-methoxytetrahydro- pyran (European Patent Application No. 0462813, Example 5 thereof; 0.547 g) and NMP (6 ml) which had been cooled to 0°C. The mixture was stirred at 0°C for 5 minutes and then heated to 145 C C for 2.2 hours with the concomitant distillation of the hexane. The mixture was cooled to ambient temperature and partitioned between ethyl acetate and water. The organic phase was washed with water, with a 0.5N aqueous sodium hydroxide solution and with brine, dried (MgSO.) and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of methylene chloride and diethyl ether as eluent. The oil so obtained was triturated under diethyl ether. There was thus obtained 4-[5-fluoro-3-(l-methyl-2-oxo-l,2,3,4-tetra- hydroquinolin-6-ylthio)phenyl]-4-methoxytetrahydropyran (0.404 g, 50%), m.p. 124-125°C; NMR Spectrum 1.8-2.1 (m, 4H), 2.55-3.0 (m, 4H), 2.99 (s, 3H) , 3.38 (s, 3H), 3.7-4.0 (m, 4H), 6.7-7.15 (m, 4H), 7.2-7.5 (m, 2H). Example 2 Using a procedure similar to that described in Example 1, a mixture of (2S, R)-4-[5-fluoro-3-(l-methyl-2-oxo-l,2,3,4-tetrahydro- quinolin-6-ylthio)phenyl]-4-methoxy-2-methyltetrahydropyran, potassium hydroxide, water and DMSO was stirred and heated to 130°C for 1 hour. The mixture was cooled to ambient temperature. Water was added and the mixture was acidified to pH5 by the addition of dilute aqueous hydrochloric acid. The mixture was extracted with diethyl ether. A solution of sodium hydroxide in methanol was added and the mixture was evaporated. The residue was partitioned between diethyl ether and water. The aqueous layer was evaporated. There was thus obtained (2S,4R)-sodium 3-{5-[5-fluoro-3-(4-methoxy-2-methyltetrahydropyran-4- yl)phenylthio]-2-methylaminophenyl}propionate as a foam (95%); NMR Spectrum (CD 3 S0CD 3 ) 1.1 (d, 3H), 1.4 (m, 1H), 1.8 (m, 3H), 2.1 (t, 2H), 2.55 (t, 2H), 2.7 (d, 3H) , 2.88 (s, 3H) , 3.45 (m, 1H), 3.7 (m, 2H), 6.5 (d, 1H), 6.55 ( , 1H) , 6.9 (m, 2H), 7.1 (d, 1H), 7.2 (m, 1H) , 7.3 (d, 1H). The (2S,4R)-4-[5-fluoro-3-(l-methyl-2-oxo-l,2,3,4- tetrahydroquinolin-6-ylthio)phenyl]-4-methoxy-2-methyltetrahydropyran used as starting material was obtained as follows:- A mixture of 6-mercapto-l-methyl-l,2,3,4-tetrahydroquinolin- 2-one (0.247 g), (2S,4R)-4-(3,5-difluorophenyl)-4-methoxy-2-methyl- tetrahydropyran (European Patent Application No. 0462813, Example 10 thereof; 0.31 g), lithium hydroxide monohydrate (0.056 g), di-(2-methoxyethyl) ether (1 ml) and NMP (4 ml) was stirred and heated to 140°C for 2 hours. The mixture was cooled to ambient temperature and partitioned between ethyl acetate and water. The organic phase was washed with water, with IN aqueous hydrochloric acid and with brine, dried (MgSO,) and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of methylene chloride and diethyl ether as eluent. The oil so obtained was triturated under diethyl ether. There was thus obtained (2S,4R)-4-[5- fluoro-3-(l-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-ylthio)phenyl]- 4-methoxy-2-methyltetrahydropyran (0.135 g, 25%), m.p. 137-139°C; NMR Spectrum 1.18 (d, 3H) , 1.4-2.2 (m, 4H), 2.50-2.96 (m, 4H), 2.98 (s, 3H), 3.37 (s, 3H), 3.65-4.15 (m, 3H), 6.65-7.50 (m, 6H). Example 3 Using a procedure similar to that described in Example 1, a mixture of (2S,4R)-4-[5-fluoro-3-(l-methyl-2-oxo-l,2,3,4-tetrahydro- quinolin-6-ylsulphonyl)phenyl]-4-methoxy-2-methyltetrahydropyran, potassium hydroxide, water and DMS0 was stirred and heated to 130°C for 1 hour. The mixture was cooled to ambient temperature. Water was added and the mixture was acidified to pH5 by the addition of dilute aqueous hydrochloric acid. The mixture was extracted with diethyl ether. A solution of sodium hydroxide in methanol was added and the mixture was evaporated. The residue was partitioned between diethyl ether and water. The aqueous layer was evaporated. There was thus obtained (2S,4R)-sodium 3-{5-[5-fluoro-3-(4-methoxy-2-methyltetra- hydropyran-4-yl)phenylsulphonyl]-2-methylaminophenyl}propionate as a hygroscopic solid (30%), m.p. 160°C (decomposes); NMR Spectrum (CD 3 SOCD 3 ) 1.1 (d, 3H) , 1.5 (m, 1H), 1.9 (m, 3H), 2.1 (t, 2H), 2.7 (m, 5H), 2.9 (s, 3H), 3.7 (m, 3H), 6.5 (d, 1H) , 7.45 (m, 2H), 7.6 (m, 2H), 7.7 (m, 1H) , 8.2 (d, 1H). The (2S,4R)-4-[5-fluoro-3-(l-methyl-2-oxo-1,2,3,4-tetra- hydroquinolin-6-ylsulphonyl)phenyl]-4-methoxy-2-methyltetrahydropyran used as starting material was obtained as follows:- Potassium peroxy onosulphate (4.4 g) was added to a mixture of (2S,4R)-4-[5-fluoro-3-(l-methyl-2-oxo-l,2,3,4-tetrahydroquinolin-6- ylthio)phenyl]-4-methoxy-2-methyltetrahydropyran (2 g), ethanol (20 ml) and water (10 ml). The mixture was stirred at ambient temperature for 18 hours. The mixture was partitioned between methylene chloride and water. The organic phase was washed with an aqueous sodium bisulphite solution, dried (MgSO,) and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of hexane and ethyl acetate as eluent. The solid so obtained was recrystallised from a mixture of hexane and ethyl acetate. There was thus obtained (2S,4R)-4-[5-fluoro-3-(l-methyl-2-oxo-1,2,3,4-tetra- hydroquinolin-6-ylsulphonyl)phenyl]-4-methoxy-2-methyltetrahydropyran (1.3 g, 60%), m.p. 110-112°C; NMR Spectrum 1.2 (d, 3H), 1.55 (m, 1H) , 1.9 (m, 2H) , 2.7 (m, 2H) , 3.0 (m, 5H), 3.4 (s, 3H), 3.9 (m, 3H), 7.1 (d, 1H) , 7.3 (m, 1H) , 7.5 (m, 1H), 7.75 (m, 2H), 7.85 (q, 1H). Example 4 Using a procedure similar to that described in Example 1, a mixture of (2S,4R)-4-hydroxy-2-methyl-4-[3-(l-methyl-2-oxo-l,2,3,4- tetrahydroquinolin-6-ylthio)phenyl]tetrahydropyran, potassium hydroxide, water and DMSO was stirred and heated to 130°C for 1 hour. The mixture was cooled to ambient temperature. Water was added and the mixture was acidified to pH5 by the addition of dilute aqueous hydrochloric acid. The mixture was extracted with diethyl ether. A solution of potassium hydroxide in methanol was added and the mixture was evaporated. The residue was partitioned between diethyl ether and water. The aqueous layer was evaporated. There was thus obtained (2S,4R)-potassium 3-{5-[3-(4-hydroxy-2-methyltetrahydropyran-4-yl)- phenylthio]-2-methylaminophenyl}propionate as a foam (25%). NMR Spectrum (CD 3 S0CD 3 CD 3 C0 2 D) 1.0 (d, 3H) , 1.5 (m, 3H) , 1.8 (m, 1H) , 2.5 (m, 2H), 2.7 (m, 2H), 3.8 (m, 3H) , 6.5 (d, 1H) , 6.8 (m, 1H), 7.0-7.4 (m, 5H). The (2S,4R)-4-hydroxy-2-methyl-4-[3-(l-methyl-2-oxo-l,2,3,4- tetrahydroquinolin-6-ylthio)phenyl]tetrahydropyran and as starting material was obtained as follows:- n-Butyl-lithium (1.5M in hexane, 40 ml) was added dropwise to a stirred solution of 1,3-diiodobenzene (19.8 g) in THF (200 ml) which had been cooled to -70°C. The mixture was stirred at -70°C for 12 minutes. (2S)-2-Methyltetrahydropyran-4-one (European Patent Application No. 0385662 (Example 20 thereof); 5.7 g) was added. The mixture was stirred, allowed to warm to ambient temperature and stirred at ambient temperature for 1 hour. The mixture was acidified by the addition of glacial acetic acid and partitioned between diethyl ether and water. The organic phase was washed with brine, dried (Na 2 S0,) and evaporated. A solution of the residue in diethyl ether (50 ml) was added to concentrated sulphuric acid (35% v/v, 200 ml) which had been cooled to 0°C. The mixture was stirred and allowed to warm to ambient temperature. The mixture was stirred at ambient temperature for 3 hours. The mixture was poured onto crushed ice and extracted with diethyl ether. The organic phase was washed with water, with a saturated aqueous sodium bicarbonate solution and with brine, dried (Na S0,) and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of hexane and ethyl acetate as eluent. There was thus obtained (2S,4R)-4-hydroxy -~A-(3-iodophenyl)-2-methyltetrahydropyran (12 g, 75%). A mixture of 6-mercapto-l-methyl-1,2,3,4-tetrahydroquinolin- 2-one (0.23 g), (2S,4R)-4-hydroxy-4-(3-iodophenyl)-2-methyltetrahydro- pyran (0.35 g), potassium carbonate (0.2 g), cuprous chloride (0.05 g) and DMF (3 ml) was stirred and heated to 120°C for 2 hours. The mixture was cooled to ambient temperature and partitioned between ethyl acetate and water. The organic phase was dried (Na«S0,) and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of hexane and ethyl acetate as eluent. There was thus obtained (2S,4R)-4-hydroxy-2-methyl-4-[3-(l-methyl-2- oxo-1,2,3,4-tetrahydroquinolin-6-ylthio)phenyl]tetrahydropyran (0.33 g), m.p. 135-137°C (recrystallised from a mixture of hexane and ethyl acetate) ; NMR Spectrum 1.21 (d, 3H) , 1.55-1.8 ( , 4H) , 2.1 (m, IH) , 2.66 (m, 2H), 2.86 (m, 2H), 3.35 (s, 3H), 3.85-4.05 (m, 3H) , 6.93 (d, IH), 7.13 ( , IH), 7.2-7.4 (m, 4H) , 7.47 (m, IH) .

Claims: CLAIMS An aniline derivative of the formula I wherein R is hydrogen, (1-4C)alkyl, halogeno-(1-4C)alkyl, cyano-(1-4C)alkyl, hydroxy-(2-4C) lkyl, amino-(2-4C)alkyl, (l-4C)alkylamino-(2-4C)alkyl, di-[(l-4C)alkyl]amino-(2-4C)alkyl or phenyl-(l-4C)alkyl, and wherein said phenyl-(l-4C)alkyl group may optionally bear one or two substituents selected from halogeno, trifluoromethyl, cyano, (l-4C)alkyl and (l-4C)alkoxy; R is hydrogen, hydroxy, (l-4C)alkyl or (l-4C)alkoxy; R is hydrogen or (l-4C)alkyl; 3 7 8 X is oxy, thio, sulphinyl, sulphonyl or a group of the formula CR R 7 8 wherein R is hydrogen or (1-4C)alkyl and R is hydrogen or 3 9 9 - (1-4C)alkyl, or X is a group of the formula NR wherein R is hydrogen 3 or (l-4C)alkyl, or X is a direct link to the 2-position of the anilino ring; the anilino ring may optionally bear a halogeno substituent; A is a direct link to X or is (l-3C)alkylene; X is oxy, thio, sulphinyl or sulphonyl; Ar is phenylene, pyridinediyl, pyrimidinediyl, thiophenediyl, furandiyl, thiazolediyl, oxazolediyl, thiadiazolediyl or oxadiazolediyl which may optionally bear one or two substituents selected from halogeno, cyano, trifluoromethyl, hydroxy, amino, (l-4C)alkyl, (l-4C)alkoxy, (l-4C)alkylamino and di-(l-4C)alkylamino; R 1 is hydrogen, (l-4C)alkyl, (3-4C)alkenyl or (3-4C)alkynyl; and 2 3 2 2 3 R and R together form a group of the formula -A -X -A - which 2 3 together with the carbon atom to which A and A are attached define a 2 3 ring having 5 or 6 ring atoms, wherein A and A , which may be the same 2 or different, each is (l-3C)alkylene and X is oxy, thio, sulphinyl, sulphonyl or imino, and which ring may bear one, two or three substituents, which may be the same or different, selected from hydroxy, (l-4C)alkyl, (l-4C)alkoxy, fluoro-(l-4C)alkyl, cyano-(1-4C)alkyl, (3-4C)alkenyl and (3-4C)alkynyl; 1 2 2 2 3 or R and R together form a group of the formula -A -X -A - which 2 together with the oxygen atom to which A is attached and the carbon 3 atom to which A is attached define a ring having 5 or 6 ring atoms, 2 3 wherein A and A , which may be the same or different, each is 2 (l-3C)alkylene and X is oxy, thio, sulphinyl or sulphonyl, and which 3 ring may bear one, two or three (1-4C)alkyl substituents, and R is (l-4C)alkyl, (2-4C)alkenyl or (2-4C)alkynyl; or a pharmaceutically-acceptable salt, ester or amide thereof. 2. An aniline derivative of the formula I as claimed in Claim 1 wherein R is methyl, ethyl or propyl; R is hydrogen or methyl; R is hydrogen or methyl; 3 7 8 7 X is oxy or thio or a group of the formula CR R wherein each of R o and R is hydrogen; A is methylene and X is oxy, or A is a direct link to X and X is oxy, thio, sulphinyl or sulphonyl; Ar is 1,3- or 1,4-phenylene which may optionally bear one or two substituents selected from fluoro, chloro, trifluoromethyl, methyl and methoxy, or Ar is 3,5-pyridinediyl, 4,6-pyrimidinediyl, 2-amino-4,6-pyrimidinediyl, 2,4- or 2,5-thiophenediyl or 2,4- or 2,5-thiazolediyl; R is hydrogen, methyl, ethyl or allyl; and 2 3 2 2 3 R and R together form a group of the formula -A -X -A - which 2 3 together with the carbon atom to which A and A are attached define a 2 3 ring having 5 or 6 ring atoms, wherein A is methylene or ethylene, A 2 is ethylene and X is oxy, and which ring may bear one or two substituents selected from methyl and ethyl; or a pharmaceutically-acceptable salt thereof. 3. An aniline derivative of the formula I as claimed in Claim 1 wherein R is methyl, ethyl or propyl; R is hydrogen or methyl; R is hydrogen or methyl; 3 7 8 7 8 X is a group of the formula CR R wherein each of R and R is hydrogen; A is methylene and X is oxy, or A is a direct link to X and X is oxy, thio, sulphinyl or sulphonyl; Ar is 1,3- or 1,4-phenylene which may optionally bear one or two substituents selected from fluoro, chloro, trifluoromethyl, methyl and methoxy, or Ar is 3,5-pyridinediyl, 4,6-pyrimidinediyl, 2-amino-4,6-pyrimidinediyl, 2,4- or 2,5-thiophenediyl or 2,4- or 2,5-thiazolediyl; R is hydrogen, methyl, ethyl or allyl; and 2 3 2 2 3 R and R together form a group of the formula -A -X -A - which 2 3 together with the carbon atom to which A and A are attached define a 2 3 ring having 5 or 6 ring atoms, wherein A is methylene or ethylene, A 2 is ethylene and X is oxy, and which ring may bear one or two substituents selected from methyl and ethyl; or a pharmaceutically-acceptable salt thereof. 4. An aniline derivative of the formula I as claimed in Claim 1 wherein R is methyl or ethyl; R is hydrogen; R is hydrogen; 3 X is oxy or CH_; 1 1 1 A is a direct link to X and X is thio or sulphonyl; Ar is 1,3-phenylene, 5-fluoro-l,3-phenylene, 2,4-thiophenediyl (with the X group in the 2-position), 2,5-thiophenediyl, 2,4-thiazolediyl (with the X group in the 2-position) or 2,5-thiazolediyl (with the X group in the 2-position); R is hydrogen or methyl; and 2 3 2 2 3 R and R together form a group of the formula -A -X -A - which 2 3 together with the carbon atom to which A and A are attached define a 2 3 ring having 5 or 6 ring atoms, wherein A is methylene or ethylene, A 2 is ethylene and X is oxy, and which ring may bear a methyl substituent 2 alpha to X ; or a pharmaceutically-acceptable salt thereof. 5. An aniline derivative of the formula I as claimed in Claim 1 4 wherein R is methyl; R is hydrogen; R is hydrogen; X 3 is CH„ ; A 1 is a direct link to X 1 and X1 is thio or sulphonyl; Ar is 1 , 3-phenylene or 5-fluoro-l , 3-phenylene; R is methyl; and 2 3 2 2 3 R and R together form a group of the formula -A -X -A - which 2 3 together with the carbon atom to which A and A are attached define a 2 3 2 ring having 6 ring atoms, wherein each of A and A is ethylene and X 2 is oxy, and which ring may bear a methyl substituent alpha to X ; or a pharmaceutically-acceptable salt thereof. 6. The aniline derivative 3-{5-[5-fluoro-3-(4-methoxytetrahydro- pyran-4-yl)phenylthio]-2-methylaminophenyl}propionic acid or a pharmaceutically-acceptable salt thereof. 7. An aniline derivative of the formula I as claimed in Claim 1 selected from:- (2S,4R)-3-{5-[5-fluoro-3-(4-methoxy-2-methyltetrahydropyran-4-yl)- phenylthio)-2-methylaminophenyl}proprionic acid; (2S,4R)-3-{5-[5-fluoro-3-(4-methoxy-2-methyltetrahydropyran-4-yl)- phenylsulphonyl]-2-methylaminophenyl}propionic acid and (2S,4R)-3-{5-[3-(4-hydroxy-2-methyltetrahydropyran-4-yl)phenylthio]-2- methylaminophenyl}propionic acid; or a pharmaceutically-acceptable salt thereof. 8. A process for the preparation of an aniline derivative of the formula I, or a pharmaceutically-acceptable salt thereof, as claimed in any one of Claims 1 to 7 which comprises:- (a) the coupling of a compound of the formula II with a compound of the formula III OR 1 Z-Ar- C— R 2 III R 3 wherein Z is a displaceable group; (b) the coupling of a compound of the formula IV 6 wherein Z is a displaceable group with a compound of the formula V; OR H- X 1 -Ar- C— R 2 (c) the coupling of a compound of the formula VI wherein Z is a displaceable group with an organometallic reagent of the formula VII O R 1 - A r - C — R 2 VII I R 3 wherein M is an alkali metal or alkaline earth metal or M represents the magnesium halide portion of a conventional Grignard reagent; (d) the hydrolysis of a compound of the formula VIII; or (e) for the production of those compounds of the formula I 1 3 2 3 wherein X or X is a sulphinyl or sulphonyl group, wherein R and R 2 2 3 2 together form a group of the formula -A -X -A - and X is a sulphinyl or sulphonyl group or wherein R 1 and R2 together form a group of the 2 2 3 2 formula -A -X -A - and X is a sulphinyl or sulphonyl group, the oxidation of a compound of the formula I wherein X 1 or X3 is a thio 2 3 group, wherein R and R together form a group of the formula 2 2 3 2 1 2 -A -X -A - and X is a thio group or wherein R and R together form a 2 2 3 2 group of the formula -A -X -A - and X is a thio group; and when a pharmaceutically-acceptable salt of a compound of the formula I is required, it may be obtained by reaction of said compound with a suitable acid or base using a conventional procedure; and when a pharmaceutically-acceptable ester of a compound of the formula I is required it may be obtained by reaction of a carboxy group within said compound with a suitable alcohol or phenol using a conventional procedure or by reaction of a hydroxy group within said compound with a suitable carboxylic acid using a conventional procedure; and when a pharmaceutically-acceptable amide of a compound of the formula I is required it may be obtained by reaction of a carboxy group within said compound with a suitable amine using a conventional procedure; and when an optically active form of a compound of the formula I is required, it may be obtained by carrying out one of the aforesaid procedures using an optically active starting material, or by resolution of a racemic form of said compound using a conventional procedure. 9. A pharmaceutical composition which comprises an aniline derivative of the formula I or a pharmaceutically-acceptable salt thereof, as claimed in any one of Claims 1 to 7 in association with a pharmaceutically-acceptable diluent or carrier. 10. The use of an aniline derivative of the formula I or a pharmaceutically-aceptable salt thereof, as claimed in any one of Claims 1 to 7 in the production of a new medicament for use in a leukotriene mediated disease or medical condition.

Inventors: EDWARDS PHILIP NEIL, EDWARDS, PHILIP, NEIL
Applicants: EDWARDS PHILIP NEIL, ZENECA LTD, ZENECA PHARMA SA, EDWARDS, PHILIP, NEIL, ZENECA LIMITED, ZENECA-PHARMA S.A.
Application year: 1994
Main classification: C07D309
IPC codes: A61K31, A61P29, A61P37, A61P43, C07D263, C07D271, C07D277, C07D285, C07D309, C07D405